Trematocidal Synthetic Perioxides

杀吸虫合成过氧化物

• 批准号: 7648067
• 负责人: Jonathan L Vennerstrom
• 金额: $ 15.81万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648067
• 关键词: Acids; Acute; Adamantane; Address; Adolescent; Adult; Affect; Bile fluid; Biological Assay; Carboxylic Acids; Cells; Characteristics; Chemicals; Chronic; Clonorchis sinensis; Country; Cyclohexanes; Data; Disease; Dose; Drug Combinations; Drug Kinetics; Drug resistance; Ensure; Enzymes; Fasciola hepatica; Fascioliasis; Feedback; Goals; Hepatic; Hepatica; Human; In Vitro; Infection; Inhibitory Concentration 50; Investigation; Lead; Libraries; Liver diseases; Measures; Metabolic; Metabolism; Modeling; Molecular Target; Morbidity - disease rate; Muscle; Myoblasts; Oral; Parasites; Peroxides; Pharmaceutical Preparations; Plant Roots; Plasmodium falciparum; Praziquantel; Prevention; Prodrugs; Property; Protein Isoforms; Rattus; Resistance development; Rural; Screening procedure; Skeletal Muscle; Staging; Surface; Testing; Toxic effect; Treatment Efficacy; Vaccines; analog; base; cytotoxicity; design; disorder prevention; drug development; flexibility; foodborne; functional group; in vitro testing; in vivo; insight; novel; process optimization; public health relevance; research study; triclabendazole

DESCRIPTION (provided by applicant): Food-borne trematodiases affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of food-borne tremotodiases, effective drugs are the only practical means of morbidity control. Importantly, new drugs for these diseases are urgently needed as praziquantel and triclabendazole are the only drugs available and the development of resistance cannot be ignored, particularly in view of the large- scale use of praziquantel in many endemic countries. At the root of this project is our discovery that several synthetic peroxides also possess strong trematocidal activity. We propose to further explore the potential of synthetic peroxides as novel trematocidal drugs. The identification of a new, broad-spectrum, orally-active synthetic peroxide trematocidal drug development candidate will minimize drug-resistance and lead to superior treatment and control options for food-borne trematodiases. Essential characteristics of a new drug development candidate include an economically-feasible and scalable synthesis, excellent oral activity, low potential for toxicity and resistance development, broad spectrum of trematocidal activity, and high efficacy against all parasite stages in the vertebrate host. More specifically, our objective is to identify a drug development candidate with 100% worm burden reductions against juvenile and adult F. hepatica and C. sinensis at doses of < 100 mg/kg and with an excellent ADME profile (predicted ER < 0.30, CYP450 IC50s > 25 5M, oral BA > 30%). To address this overarching objective, we propose the following three specific aims: Specific Aim 1: To synthesize and characterize a focused and structurally diverse library of synthetic peroxides. Specific Aim 2: To assess trematocidal activity and selectivity of target synthetic peroxides against two major human food-borne trematode species, Fasciola hepatica and Clonorchis sinensis. Specific Aim 3: To determine metabolism and pharmacokinetic parameters and initiate mechanism of action studies for selected synthetic peroxides. PUBLIC HEALTH RELEVANCE Food-borne trematodiases, caused by infection with liver flukes, affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of these diseases, new drugs are urgently needed. Praziquantel and triclabendazole are the only drugs now available and the development of resistance cannot be ignored, particularly in view of the large-scale use of praziquantel in many endemic countries. In this proposal, we propose to identify a new broad-spectrum orally-active trematocidal drug development candidate.

描述（由申请人提供）：食源性疾病影响数以亿计的人，特别是发展中国家的农村贫困人口。由于目前没有疫苗，而且不太可能在短期内获得预防食源性吸虫病的疫苗，有效的药物是控制发病率的唯一实际手段。重要的是，迫切需要治疗这些疾病的新药，因为吡喹酮和三氯苯达唑是唯一可用的药物，而且耐药性的发展不容忽视，特别是考虑到吡喹酮在许多流行国家的大规模使用。这个项目的根本原因是我们发现几种合成过氧化物也具有很强的杀虫活性。我们建议进一步探索合成过氧化物作为新型治疗药物的潜力。鉴定一种新的、广谱的、口服活性的合成过氧化氢杀虫药物将最大限度地减少耐药性，并为食源性疾病提供更好的治疗和控制选择。新药开发候选药物的基本特征包括经济上可行和可扩展的合成，良好的口服活性，低毒性和耐药发展潜力，广谱杀虫活性，以及对脊椎动物宿主所有阶段的寄生虫都有效。更具体地说，我们的目标是确定一种候选药物，在剂量< 100 mg/kg的情况下，可以100%减少幼年和成年肝炎F.和C. sinensis的蠕虫负担，并具有出色的ADME谱（预测ER < 0.30, CYP450 ic50 > 25 5M，口服BA > 30%）。为了实现这一总体目标，我们提出以下三个具体目标：具体目标1：合成和表征一个集中的和结构多样化的合成过氧化物库。特异性目的2：评价目标合成过氧化物对肝片吸虫和华支睾吸虫两种主要食源性吸虫的杀虫活性和选择性。特定目的3：确定代谢和药代动力学参数，并启动选定的合成过氧化物的作用机制研究。由肝吸虫感染引起的食源性吸虫病影响到数亿人，特别是发展中国家的农村穷人。由于目前没有疫苗，而且不太可能在短期内获得预防这些疾病的疫苗，因此迫切需要新药。吡喹酮和三氯苯达唑是目前仅有的药物，耐药性的发展不容忽视，特别是考虑到吡喹酮在许多流行国家的大规模使用。在本提案中，我们建议确定一种新的广谱口服活性治疗药物开发候选药物。

项目成果

Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni.

• DOI: 10.1016/j.actatropica.2011.02.003
• 发表时间: 2011-04
• 期刊: ACTA TROPICA
• 影响因子: 2.7
• 作者: Kirchhofer, Carla;Vargas, Mireille;Braissant, Olivier;Dong, Yuxiang;Wang, Xiaofang;Vennerstrom, Jonathan L.;Keiser, Jennifer
• 通讯作者: Keiser, Jennifer

Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.

• DOI: 10.1021/jm100226t
• 发表时间: 2010-05-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhao Q;Vargas M;Dong Y;Zhou L;Wang X;Sriraghavan K;Keiser J;Vennerstrom JL
• 通讯作者: Vennerstrom JL

Tetrasubstituted pyrazinones derived from the reaction of praziquantel with N-bromosuccinimide.

由吡喹酮与N-溴代琥珀酰亚胺反应衍生的四取代吡嗪酮。

• DOI: 10.1016/j.tetlet.2014.06.083
• 发表时间: 2014
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Zhao,Qingjie;Wang,Chunkai;Ezell,EdwardL;Dong,Yuxiang;Vennerstrom,JonathanL
• 通讯作者: Vennerstrom,JonathanL

The activity of dispiro peroxides against Fasciola hepatica.

二螺过氧化物对肝片形吸虫的活性。

• DOI: 10.1016/j.bmcl.2011.07.024
• 发表时间: 2011
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Wang,Xiaofang;Zhao,Qingjie;Vargas,Mireille;Dong,Yuxiang;Sriraghavan,Kamaraj;Keiser,Jennifer;Vennerstrom,JonathanL
• 通讯作者: Vennerstrom,JonathanL